The primary objective of this project is to develop new agents for the treatment of cancers in children and young adults with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. Clinical trials are conducted as single site and multi-site trials. In addition, we are collaborating with the Children's Oncology Group (COG), the sarcoma cooperative group SARC, and the NF Clinical Trials Consortium in the development and conduct of trials. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, and tumors with no known effective medical therapy such as alveolar soft part sarcoma or malignant peripheral nerve sheath tumors (MPNST). This work is performed through the Pharmacology and Experimental Therapeutics (PET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) Example of collaboration with the Children's Oncology Group (COG): Phase I and II trial of cabozantinib (XL184) for refractory solid tumors and select solid tumor strata. Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including primarily MET, VEGFR2 and RET and to a lesser extent KIT and TIE-2. RET inhibition provided the rationale for our development of cabozantinib for pediatric medullary thyroid carcinoma (MTC). However, cabozantinib also targets RTKs that are overexpressed in a variety of pediatric cancers including, VEGFR2 in pediatric sarcomas, MET in osteosarcoma, glioma, and papillary thyroid carcinoma. We thus collaborated with the COG Phase I/Pilot Consortium in the development of cabozantinib in a phase I trial with an arm specifically for MTC and an arm for refractory solid tumors including brain tumors. This trial has completed enrollment and has achieved the primary objectives. Based on promising results with several objective responses and prolonged disease stabilization we developed a phase II trial of cabozantinib for several solid tumor strata in collaboration with the COG (2) Example of collaboration with the sarcoma cooperative group SARC and with the DoD sponsored NF Clinical trials Consortium: The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing for both patient populations. I directed a SARC coordinated multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab. This trial received funding through a Department of Defense Clinical Trial Award. Results of this trial were just published. Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST (PI: AeRang Kim, Co-PI: Brigitte Widemann). This trial is also complete and the manuscript under review. Based on promising preclinical results, a phase II trial combining the mTOR inhibitor sirolimus with a MEK inhibitor will soon open for enrollment (PI: AeRang Kim, Co-PI: Brigitte Widemann). Close collaboration of SARC, the DOD sponsored NF Consortium, and investigators invested in developing effective therapies for MPNST has demonstrated that the timely conduct of histology specific trials is feasible. 3) Example for collaboration with the NCI CCR Developmental Therapeutics Clinic: We are collaborating with Dr. Alice Chen by enrolling children with refractory cancers such as alveolar soft part sarcoma, on primarily adult clinical trials directed by her. The pediatric portion of the trial is complete and the manuscript under review. Similarly, Dr. Chen will evaluate adult patients on Pediatric Oncology Branch trials. This ensures that children and adults with rare tumors get optimal access to targeted therapies. We have developed a pediatric-adult rare tumor protocol with the goal to perform in depth natural history studies in select rare tumors. The NCI POB and my Section have a leadership role in 2 NCI CCR Initiatives: The NCI CCR Rare Tumors Initiative (RTI) fosters focused collaborations between basic and clinical researchers at NCI (CCR and DCEG), as well as extramural investigators. The Rare Tumor Patient Engagement Network (RTPEN), supported by the Cancer Moonshot, aims to connect patients and investigators through shared infrastructure and networks, accelerate the understanding of rare tumors and develop clinical trials for rare tumors through these national and international collaborations of patients, advocates, clinicians, clinical and basic researchers, and other stakeholders. The long-term goal of the RTPEN is to effectively study the biology and clinical course of rare tumors, translate these findings to improve care and treatment and to ensure that all patients have access to clinical trials which may benefit them. In a collaboration with the NCI/DCEG we have developed a rare tumor protocol, which will serve CCR and DCEG investigators. The primary objective of this protocol is to engage patients with a set of rare tumors, to study their rare tumor patients and their tumor and biologic samples comprehensively in order to develop better therapies. This rare tumor effort will have extramural collaborators and also engage advocacy groups. The rare tumor protocol is open for enrollment and we are in the process of adding extramural sites. As a subprotocol to the master rare tumor protocol we have developed a protocol for patients with chordoma, which is also open for enrollment. We hosted an inaugural pediatric chordoma clinic in April 2019, which brought together patients and families, members of the chordoma foundation, and experts in the care of chordoma patients. Additional sub protocols are in development. Finally, we developed a proposal to comprehensively study RASopathies in children and young adults. RASopathies are genetic disorders characterized by germline mutations in RAS pathway genes. These syndromes, such as neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome, and Costello syndrome (CS), have a widely variable incidence (1:1000 NS -1:300,000 CS) are usually first diagnosed in children and exhibit a wide variety of manifestations, including life-threatening congenital heart disease, failure to thrive, and increased risk of development of pediatric cancers such as sarcomas, leukemias, and CNS tumors (up to 42-fold increased risk compared to the general population). No approved medical therapies exist for RASopathies. This is a collaborative effort of the NCI CCR, NCI DCEG as well as extramural investigators and advocacy groups and will include the development of a RASopathy natural history study, the development of treatment trials directed at RASopathy manifestations including tumors associated with RASopathies, and a population genomics approach. This project is described in more detail in Dr. Marielle Yohe's report.